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Esomeprazole‐induced healing of gastroesophageal reflux disease is unrelated to the genotype of CYP2C19 : Evidence from clinical and pharmacokinetic data
Author(s) -
Schwab Matthias,
Klotz Ulrich,
Hofmann Ute,
Schaeffeler Elke,
Leodolter Andreas,
Malfertheiner Peter,
Treiber Gerhard
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.08.017
Subject(s) - esomeprazole , cyp2c19 , omeprazole , gerd , gastroenterology , proton pump inhibitor , medicine , reflux , pharmacokinetics , genotype , pharmacology , disease , biology , metabolism , cytochrome p450 , biochemistry , gene
Background The clinical outcome of acid‐related disorders treated by proton pump inhibitors (PPIs) might be dependent on the polymorphically expressed cytochrome P450 (CYP) 2C19, which is involved in PPI metabolism. We tested whether esomeprazole‐induced healing of gastroesophageal reflux disease (GERD) is related to CYP2C19 genotype. Methods Two hundred five patients with GERD (Los Angeles classification grade A or B) were included in a case‐control study according to endoscopic outcome (healed versus unhealed group, matched for confounders) after treatment with 40 mg esomeprazole daily for 4 weeks. The frequency of CYP2C19 genotypes was determined as the primary outcome measure for both groups. In a second trial plasma levels of esomeprazole and corresponding CYP2C19 and CYP3A4 metabolites (5‐hydroxyomeprazole and omeprazole sulfone) were monitored in 10 CYP2C19 wild‐type patients with GERD after the first and last doses (day 7) of 40 mg esomeprazole daily to calculate metabolic ratios. Results CYP2C19 wild‐type (n = 148) and heterozygous (n = 51) or homozygous variant (n = 6) patients did not differ with respect to baseline characteristics. The frequency distribution of CYP2C19 genotypes was not different between patients with complete (75/100) and incomplete (73/105) healing ( P = .65). When a single esomeprazole dose and multiple dosing were compared, the low contribution of CYP2C19 to the elimination of esomeprazole decreased further by 50%. In contrast, the CYP3A4‐dependent formation of omeprazole sulfone increased by 40%, and consequently, the metabolic ratio of omeprazole sulfone to 5‐hydroxyomeprazole was elevated from 7.9 to 19.3 ( P = .0004). Conclusion In contrast to other PPIs, esomeprazole‐induced healing of GERD is unrelated to the CYP2C19 genotype, which can be explained by the metabolic shift toward the CYP3A4‐mediated pathway. Clinical Pharmacology & Therapeutics (2005) 78 , 627–634; doi: 10.1016/j.clpt.2005.08.017